Azabicyclo[3.1.0]hexane compounds have use as pharmaceuticals. For example, 3-azabicyclo[3.1.0]hexane derivatives can bind to opiate receptors such as mu, kappa and delta opioid receptors. This ability makes them useful in treating diseases modulated by opiate receptors such as irritable bowel syndrome, constipation, nausea, vomiting; and including pruritic dermatoses such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors have also been indicated in treating eating disorders, opiate overdoses, depression, smoking, and alcohol addition and dependence, sexual dysfunction, shock, stroke, spinal damage and head trama.
3-azabicyclo[3.1.0]hexane derivatives, their synthesis and use as opioid derivatives, are disclosed in WO 00/39089 and U.S. patent application Ser. No. 10/278,142, filed Oct. 22, 2002 entitled “3-Azabicyclo[3.1.0]hexane Derivatives.”
Fabrication of azabicyclo[3.1.0]hexane compounds for pharmaceutical usage typically entails formation of a related salt. Oftentimes, however, an unwanted suspension of fine oil droplets is created during manufacture which adheres to the vessel, causing disruption of operations that can be particularly burdensome in large scale, bulk synthesis of such compounds. Ameliorating this is the use of select solvents such as tetrahydrofuran (THF) as a medium in which salt synthesis occurs. While THF redresses the oiling and adherence problem, it is often retained with the final azabicyclohexane product—by entrainment, for example—at levels that are unacceptable in a clinical use setting. Efforts to reduce the amount of THF, and indeed other process-related impurities, from the azabicyclo[3.1.0]hexane compound have met with only partial success, e.g. vacuum drying, employing a smaller particle size.
Thus there is a need for a process to prepare an azabicyclo[3.1.0]hexane compound having reduced impurities—particularly process-related impurities such as THF and the like—in amounts sufficient to permit clinical use, without breaking the salt to free base form and without adding undue steps to the preparation.